This proposal describes a five-year research training program that will allow Dr. Hill to achieve his long-term goal of becoming an independent clinically-oriented academic researcher, focusing on viral infections in immunocompromised hosts. Dr. Hill's goal is to improve hematopoietic cell transplantation (HCT) outcomes by advancing understanding of diseases associated with human herpesvirus 6 (HHV-6) and other viruses. He will apply this knowledge to develop diagnostic techniques and therapeutic strategies that mitigate complications due to viral infections in immunocompromised hosts. This proposal builds upon his clinical training in infectious diseases and methodology for clinical research in this field. Dr. Hill provides a detailed plan to improve his knowledge of advanced epidemiology, biostatistics, molecular virology, and conducting prospective studies. This proposal incorporates the expertise of an outstanding group of mentors, including experts in infectious diseases, epidemiology, laboratory medicine, pathology, and statistics, who are dedicated to ensuring the success of this project and the development of Dr. Hill's career as an independent clinical researcher. The first aim of this proposal involves a large retrospective study to determine the clinical significance of HHV- 6 in lower respiratory tract disease (LRTD) after HCT. Dr. Hill will test archived bronchoalveolar lavage fluid (BALF) for HHV-6 DNA with quantitative PCR. Based on these results, review of patient records, and molecular testing of blood and lung tissue, he will describe the epidemiology, risk factors, and clinical impact of HHV-6 in HCT recipients with LRTD. His second aim will employ prospective collection and processing of BALF and whole blood for viral and host gene expression studies using reverse transcription PCR and RNA- seq, respectively. These results will further characterize the molecular pathogenesis of HHV-6, inform the significance of HHV-6 DNA detection, and facilitate patient risk-stratification. The third aim will capitalize on novel molecular techniquesto identify and study a large retrospective cohort of HCT recipients with chromosomally integrated HHV-6, a poorly understood condition affecting 1-2% of the general population. While generally believed to be benign, preliminary evidence suggests that chromosomally integrated HHV-6 can be the source of pathologic HHV-6 reactivation and may warrant routine pre-HCT screening. Through accomplishing the aims in this proposal, Dr. Hill will address critical gaps in our knowledge of the importance of HHV-6 infection in HCT recipients and our ability to use clinical characteristics and novel molecular diagnostics to predict disease. Given that effective but potentially toxic medications are available to treat HHV-6, a better understanding of this virus will provide the basis to develop diagnostic, prevention, and treatment strategies. Ultimately, thi proposal will allow Dr. Hill to build a larger research program to advance understanding of viral infections in immunocompromised hosts and improve patient outcomes.